Epilepsy is a symptom of excessive temporary neuronal discharge, due to intracranial or extracranial causes; it is characterized clinically by discrete episodes, which tend to be recurrent, in which there is a disturbance of movement, behavior, perception and/or consciousness. The precise mechanism involved in the excessive neuronal discharge of epilepsy remains unknown. Nerve tissue is electronically excitable and this excitability is influenced by many factors. The relative tendency individuals to experience excessive neuronal discharge leading to seizures is referred to as the seizure threshold of the brain. In normal individuals possessing a high threshold and never experience abnormal periods of neuronal activity. Individuals with low threshold will periodically experience those episodes associated with epileptic seizures. The causes of the seizures may be from lowered neuronal resting potential due to inherent abnormalities in cellular ion gradients or in excitatory and inhibitory neuronal transmitter systems. Seizure spread may also be potentiated by damage to inhibitory neurons due to traumatic, infective, vascular or neoplastic causes. Hyperexcitability of neurons can also be a chronic effect caused by pyrexia, hypoxia, hypoglycemia, overhydration, alkalosis, withdrawal of barbiturates or alcoholism. In addition, seizures may be induced by convulsant drugs, electric shock, auditory or visual stimulus and physical and emotional stress.
Pharmaceutical agents used for the control of epilepsy fall into a variety of chemical classes including, but not limited to, acridines, amphetamines, barbiturates, carbamates, benzodiazepines, butyric acid derivatives, glutamic acid derivatives, valproic acid derivatives, ureas, hydantions, oxazolidinediones, succinimides, sulfonamides and hydrazones [see J. A. Vida, "Anticonvulsants", Academic Press, New York, 1977]. Convulsant seizures have been found to originate locally (at primary focii) in the brain and spread to other regions. The mode of action of most anticonvulsant drugs involves either the suppression of preconvulsant stimulus at the primary focus or inhibition of the spread of the excessive electrical activity to other brain regions [see. F. Morrell, W. Bradley and M. Ptashe, Neurology, 9,492 (1959)]. The majority of clinically useful anticonvulsant have a cyclic ureide structure. ##STR2##
These include the important drugs phenobarbital and diphenylhydantoin (Dilantin) Other clinically important which do not possess the cyclic ureide structure are primadone, benzodiazepines and carbamazepine. ##STR3##
Carbamazepine (5-carbamyl-5H-dibenzo[b,f]azepine) is a major anticonvulsant drug for the treatment of complex partial and generalized tonicclonic seizures. Carbamazepine is often used in patients who have not responded satisfactorily to treatment with other agents. It shows good activity and low acute and motor toxicity. Although it has been implicated in bone marrow suppression only one case of toxic overdose has been reported. The low toxicity of carbamazepine may be due to its low bioavailability.
Recent studies have indicated that carbamazepine may possess the ability to restrict cocaine craving in cocaine addicts. In one study 59% of the addicts taking the medication were able to abstain from cocaine for a prescribed period compared to 17% who received a placebo.
Recently, MK-801, a new anticonvulsant of novel structure, has shown potential usefulness for seizures of local origin and major generalized seizures. MK-801 is essentially free of the usual sedative side effects common to most of the commonly proscribed anticonvulsants [Clineschmidt et al Drug Dev. Res2, 123 (1982)]. Psychological disturbances in some of the patients in the clinical trials may be a consequence of the high affinity of the drug for phencyclidine binding sites in the central nervous system. ##STR4##